Our overall objective is to solve the problem of how proteins fold into their native conformations and then (e.g. as enzymes) interact with substrates and other ligands. For this purpose, we are using the methodology of protein chemistry, and developing and applying experimental and theoretical techniques (to be used together) to provide an understanding of the internal interactions that stabilize native proteins in aqueous solution. The experimental work involves the use of immunochemistry, flash photolysis, fluorescence energy transfer, proteolytic digestion, Raman spectro- scopy, and recombinant DNA procedures to determine the pathways of folding of ribonuclease. When this work is finished, we will carry out similar studies of lysozyme and pancreatic trypsin inhibitor. The theoretical work involves the use of empirical potentials (including the effect of hydration), in various computational approaches to study the interactions involved in protein folding (bovine pancreatic trypsin inhibitor and leukocyte interferon). An understanding of the interactions in proteins is of potential applicability to the elucidation of the role of conformation in biological processes, e.g. the undesirable association of sickle- cell hemoglobin, or the induction of an oncogene product whose properties involve a conformational change when only one amino acid in the sequence is changed.